Loss of RB1 and TP53 induces a neuroendocrine phenotype that confers resistance to antiandrogen therapy.

  • Major finding: Loss of RB1 and TP53 induces a neuroendocrine phenotype that confers resistance to antiandrogen therapy.

  • Mechanism: The absence of RB1 and TP53 causes derepression of stem cell reprogramming factors like SOX2 and EZH2.

  • Impact: Preclinical modeling of prostate cancer lineage plasticity suggests ways to overcome antiandrogen resistance.

A subset of patients with castration-resistant prostate cancer (CRPC) who relapse following treatment with antiandrogen therapy have tumors with neuroendocrine features, but how this lineage plasticity arises and confers antiandrogen resistance is unclear. Noting that TP53 and RB1 are concurrently altered in up to 74% of metastatic CRPCs with neuroendocrine-like histology as opposed to only 5% of primary tumors, Mu and colleagues examined the effect of combined TP53 and RB1 knockdown or deletion in antiandrogen-sensitive human prostate cancer cells. Combined TP53 and RB1 loss conferred enzalutamide resistance and led to a significant increase in expression of neuroendocrine markers without the restoration of androgen receptor signaling that is commonly observed in CRPC. Instead, the reprogramming factor SOX2 was significantly upregulated in RB1- and TP53-altered tumors, and SOX2 knockdown reversed the expression of neuroendocrine lineage markers and restored enzalutamide sensitivity. In a related study, Ku, Rosario, and colleagues found that co-deletion of Rb1 in Pten-deficient prostate cancer mouse models promoted metastasis and lineage plasticity, with lineage-tracing experiments suggesting that neuroendocrine-like cells were derived from preexisting luminal cells. Consistent with the observations in human prostate cancer cells, the additional loss of Trp53 function in this model accelerated the onset of neuroendocrine marker expression and conferred resistance to antiandrogen therapy. Gene expression profiling indicated that the Pten/Rb1/Trp53-deficient tumors were similar to human neuroendocrine prostate cancer variants and showed increased expression of Sox2 as well as Ezh2, which encodes a histone H3K27 methyltransferase that plays a key role in epigenetic reprogramming to a stem cell-like state. Inhibition of EZH2 significantly decreased neuroendocrine marker expression and sensitized mouse and human prostate cancer cells to enzalutamide. Together, these studies illustrate that lineage plasticity induced by combined loss of RB1 and TP53 drives resistance to antiandrogen therapy and suggest epigenetic therapies to reverse lineage switching may be beneficial for patients with neuroendocrine-like CRPC.

Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 2017;355:84–8.

Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017;355:78–83.

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